A family of receptors that mediate signaling through tyrosine kinases includes a subfamily of at least four members: HER1 also designated epidermal growth factor receptor (EGFR) is encoded by the ErbB1 gene; HER2 or HER2/neu encoded by the ErbB2 gene, HER3, encoded by the ErbB3 gene and HER4, encoded by ErbB4. Each of these receptors has a multiplicity of synonyms and in the present application, the “HER” terminology and ErbB terminology will be used interchangeably for all the factors, whether discussing protein or nucleic acids.
The primary natural ligand for the receptor encoded by ErbB3 is heregulin (HRG), a polypeptide that, when bound to HER3 induces a conformational change that promotes dimerization of HER3 with HER2 through the extracellular domains of each activating the signaling cascade, as shown in FIG. 1A. A similar dimerization is stimulated by the ligand for the HER1 receptor, Epidermal Growth Factor (EGF), which also activates a signaling cascade intracellularly.
Antibodies, including monoclonal antibodies to HER3 have been prepared. U.S. Pat. No. 5,480,968 discloses antibodies that bind specifically to ErbB3 and do not bind to ErbB2 or ErbB1. U.S. Pat. No. 5,968,511 discloses and claims antibodies that bind to HER3 and reduce heregulin-induced formation of an HER2-HER3 protein complex in cells that express both of these receptors or which antibodies increase the binding affinity of heregulin for ErbB3 protein or which reduce activation of the downstream signaling. Although only murine antibodies are prepared, humanized antibodies are also claimed.
Published U.S. application 2004/0197332 describes and claims anti-HER3 antibodies that downregulate the expression of HER3. PCT Publication WO2007/077028 describes antibodies that bind to HER3 that are produced in XenoMouse® and are thus fully human by sequence. Most of these antibodies are described as binding to the major ligand binding domain (L2) of the extracellular domain of HER3, but the binding is destroyed if the three-dimensional structure of the extracellular domain is disrupted. Further, the antibodies described in this publication compete with HRG for binding to HER3.